Optivia’s Opti-TargetTM Transporter Services Panel, consists of a wide variety of validated and novel transporter targets implicated in diseases, toxicity, and tissue targeting. Optivia offers both rapid, low-cost compound screening and comprehensive transporter profiling services to help you discover new classes of transporter-targeted therapeutics, and assist you in adopting a transporter-conscious strategy to improve drug response and safety.
Transporters are a class of over 400 membrane proteins that tightly regulate cross-membrane transport of nutrients, signaling molecules, and xenobiotics. Transporters play a critical role in drug response and toxicity, which has led to an increase in regulatory requests for assessing transporter mediated drug-drug interactions (DDIs). Aberrant transporter activity leads to or is associated with a variety of diseases, including cancer, neurological disorders, and diabetes. Therefore, rational design of transporter-targeting molecules represents an enormous opportunity for developing new therapeutic and diagnostic agents with novel mechanisms of action and improved efficacy and safety. This is demonstrated by an increasing number of approved and experimental drugs, as well as diagnostic agents acting on various transporters, such as sertraline (depression), canagliflozin (diabetes), ivacaftor (cystic fibrosis), lesinurad (gout), and 18F-FDG (cancer imaging).
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Opti-Target™ Panel: Transporters as Therapeutic, Toxicity, and Delivery Targets
|Transporter||Physiological role||Gene||Major tissue distribution||Related disease/ADR||Examples of interacting xenobiotics||Available Species|
|ASBT||Bile acid uptake||SLC10A2||ileum, kidney, biliary tract (apical)||hypertriglycerimaemia, constipation, cholestatic liver diseases, NASH, primary bile acid malabsorption||elobixia, LUM001, SHP626, A4250||Human|
|asc-1||Amino acid transport||SLC7A10||brain, heart, placenta, skeletal muscle and kidney||learning and memory impairment, schizophrenia||BMS-466442||Human|
|ASCT2||Amino acid transport||SLC1A5||lung, skeletal muscle, large intestine, kidney, testis, adipose tissue, tumor cells||cancer||GPNA, ketamine||Human|
|BSEP||bile acid efflux||ABCB11||Liver||PFIC II, drug induced cholestasis and hepatitis||troglitazone, rifampicin, benzbromarone, bosentan, cyclosporine A||Human, rat, dog|
|CNT1||Nucleoside uptake||SLC28A1||liver, kidney, small intestine, tumor cells||cancer, infectious diseases||gemcitabine, cytarabine, azacitidine, zalcitabine, floxuridine||Human, rat|
|CNT2||Nucleoside uptake||SLC28A2||kidney (apical membrane), liver, heart, brain, placenta, pancreas, skeletal muscle, colon, rectum, small intestine, lymphocytes, tumor cells||cancer, infectious diseases||ribavirin, cladribine, didanosine, fludarabine, clofarabine, floxuridine, acacitidine, cladribine||Human, rat|
|CNT3||Nucleoside uptake||SLC28A3||pancreas, trachea, bone marrow, and mammary gland, intestine, brain, heart, prostrate, liver, tumor cells||cancer, infectious diseases||gemcitabine, azacitidine, mercaptopurine, fludarabine, clofarabine, cladribine, floxuridine||Human, rat|
|DAT||Neurotransmission||SLC6A3||brain (dopaminergic neurons), gut||Parkinson disease, Tourette syndrome, ADHD, addiction, major affective disoorders||altropane, vanoexerine, difluoropine, iometopane, DBL-583, GBR-12783, RTI-229, 11C-PE2I||Human|
|EAAT1||Neurotransmission||SLC1A3||brain (astrocytes, Bergmann glia), heart, skeletal muscle, placenta||Alzheimer's disease, Huntington's disease, epilepsy, cerebellar ataxia type 7, schizophrenia, excitotoxicity||Riluzole, l-trans-PDC, HIP-A, MPDC,TFB-TBOA, UCPH-101||Human|
|EAAT2||Neurotransmission||SLC1A2||brain (astrocytes, Bergmann glia, neurons), liver, pancreas||amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, epilepsy, ischemia, schizophrenia, excitotoxicity||Dihydrokainic acid, SYM-2081, WAY-213613,l-trans-PDC||Human|
|ENT1||Nucleoside transport||SCL29A1||heart, brain, mammary gland, erythrocytes and placenta, tumor cells||cancer, infectious diseases||gemcitabine, 5-FU, zalcitabine, cytarabine, fludarabine,cladribine, azacitidine, pentostatin, decitabine||Human|
|ENT2||Nucleoside transport||SLC29A2||skeletal muscle, liver, lung, placenta, brain, heart, kidney, ovarian tissues||cancer, infectious diseases||zidovudine, zalcitabine, cytarabine, fludarabine, 5-FU, azacitidine, pentostatin, decitabine, cladribine||Human, rat|
|ENT4/PMAT||Nucleoside transport and extrasynaptic reuptake||SLC29A4||heart, brain, skeletal muscle||depression, schizophrenia, bipolar disorder||trazodone, decynium-22||Human|
|GAT1||Neurotransmission||SLC6A1||central and peripheral neurons (GABAergic neurons)||Epilepsy, schizophrenia, ADHD||tiagabine, nipecotic acid, deramciclane, hyperforin, riluzole, SKF-89976A, NNC-711, SNAP-5114, CI-966||Human|
|GAT2||Neurotransmission||SLC6A13||brain (meninges, ependyma, choroid plexus), retina, liver, kidney||Epilepsy||tiagabine, _-Alanine, nipecotic acid, riluzole, NNC05-2090, SKF 89976A||Human|
|GAT3||Neurotransmission||SLC6A11||brain (GABAergic neurons)||Epilepsy||tiagabine, _-Alanine, nipecotic acid, riluzole, SKF 89976A||Human|
|GLYT1||Neurotransmission||SLC6A9||brain, retina, liver, spleen, kidney, pancreas, uterus, stomach, lung, placenta, intestine||schizophrenia||Bitopertin, PF-04958242||Human|
|NET||Neurotransmission||SLC6A2||brain (non adrenergic neuronal somata, axons, dendrites), peripheral nervous system, adrenal gland (chromaffin cells), placenta||depression, orthostatic intolerance, anorexia nervosa, cardiovascular disorders, ADHD||atomoxetine, reboxetine, desipramine,edivoxetine, viloxazine, maprotiline, nisoxetine, 123I-MIBG, 11C-HED||Human|
|OATP1B1||hepatic uptake of bilirubin and a variety of anionic drugs||SLCO1B1||liver (hepatocytes)||statin-induced myopathy, hyperbilirubinemia, rotor syndrome||cyclosporine A, rifampicin, gemfibrozil, ritonavir/lopinavir||Human|
|OATP1B3||hepatic uptake of bilirubin and a variety of anionic drugs||SLCO1B3||liver (hepatocytes)||unconjugated hyperbilirubinemia, Rotor syndrome||cyclosporine A, rifampicin, ritonavir/lopinavir||Human|
|OCT2||cation uptake||SLC22A2||kidney, small intestine, lung, placenta, thymus, brain (neurons, blood-brain barrier), inner ear||cytotoxicity of cisplatin, oxaliplatin and picoplatin||cisplatin, oxaliplatin, picoplatin||Human, rat|
|OCT3||cation uptake; extrasynaptic reuptake||SLC22A3||heart, skeletal muscle, brain (neurons, glial cells, plexus choroideus), small intestine, liver, lung, kidney, urinary bladder, mammary gland, skin blood vessels||Prostate cancer, coronary heart disease, obsessive compulsive disorder, depression||oxaliplatin, picoplatin, tetrabenazine, trazodone||Human, rat|
|OCTN1||ergothioneine uptake||SLC22A4||kidney, intestine, spleen, heart, skeletal muscle, brain, mammary gland, thymus, prostate, airways, testis, eye, fetal liver, sperm, immune cells||Rheumatoid arthritis, Crohn's disease||verapamil, quinidine, propafenone, clofilum||Human|
|OCTN2||carnitine uptake||SLC22A5||skeletal muscle, kidney, prostate, lung, pancreas, heart, small intestine, adrenal gland, thyroid gland, liver, etc.||Primary systemic carnitine deficiency, Crohn's disease||verapamil, quinidine, valproate, cephaloridine, pyrilamine||Human|
|PCFT||Vitamin transport||SLC46A1||small intestine, choroid plexus, kidney (proximal tubule), liver (sinusoidal), placenta||hereditary folate malabsorption, cancer||methotrxate, pemetrexed, bromosulfophthalein||Human|
|PEPT1||Peptide uptake||SLC15A1||small intestine, kidney, pancreas, bile duct, liver||inflammatory bowel disease||glycylsarcosine, bestatin, y-ALA, cephalexin, valacyclovir, cyclacillin, losartan||Human|
|PEPT2||Peptide uptake||SLC15A2||apical surface of epithelial cells from kidney and choroid plexus; neurons, astrocytes (neonates), lung, mammary gland, spleen, enteric nervous system||lead exposure||cefaclor, glycylsarcosine, bestatin, cephalexin, valacyclovir, losartan||Human|
|RFC||Vitamin transport||SLC19A1||ubiquitous||cancer||methotrxate, pemetrexed, tomudex,|
|SERT||Neurotransmission||SCL6A4||brain, peripheral nervous system, placenta, epithelium cells, platelets||anxiety, depression, autism gastrointestinal disorders, premature ejaculation, obesity, schizophrenia OCD||sertraline, fluvoxamine, fluoxetine, citalopram, zimelidine, dapoxetine, paroxetine, escitalopram, 123I-ADAM||Human|
|SGLT2||Glucose transport||SLC5A2||kidney, brain, liver, heart muscle, thyroid, salivary glands||Type II Diabetes, familial renal glucosuria||canagliflozin, dapagliflozin, empagliflozin, tofogliflozin, ipragliflizin, remogliflozin, sotagliflozin, ertugliflozin||Human|
|SNAT1||Amino acid transport||SLC38A1||brain, retina, heart, placenta, adrenal gland||Suicidal behavior, cancer||MeAIB||Human|
|SNAT2||Amino acid transport||SLC38A2||ubiquitous||Schizophrenia, cancer||MeAIB||Human|
|THTR1||Vitamin transport||SLC19A2||ubiquitous||thiamine-responsive megaloblastic anemia syndrome||fedratinib, amprolium, pyrithiamine, oxythiamine||Human|
|THTR2||Vitamin transport||SLC19A3||ubiquitous||biotin-responsive basal ganglia disease, Wernicke's encephalopathy||fedratinib, amprolium, pyrithiamine, oxythiamine||Human|
|URAT1||Uric acid reneal tubular reabsorption||SLC22A12||kidney||renal hypo-uricemia, gout||Lesinurad, RDEA3170, KUX-1151, benzbromarone||Human|
|xCT||Amino acid transport and neurotransmission||SLC7A11||macrophages, brain, retinal pigment cells, liver, kidney, tumor cells||cancer, epilepsy, neurodegenerative diseases||sulfasalazine, erastin, BAY-94-9392, BMAA||Human|
Transporter-Targeting Strategies and Examples
Transporters As Therapeutic Targets
Many transporters are important modulators of the trafficking and homeostasis of signaling molecules and nutrients. Thus, these transporter proteins themselves represent attractive targets in the treatment of various diseases. Therapeutic intervention of such transporters, either through inhibition or enhancement of activities, has produced numerous drugs. For instance, neurotransmitter reuptake transporters, such as SERT, DAT, NET, and GATs, are classical targets of many blockbuster drugs that treat mental and neurological disorders, including depression, schizophrenia, epilepsy, and ADHD. Additionally,SGLT2 is the target of the diabetes drug canagliflozin, CFTR is the target of ivacaftor for treating cystic fibrosis, NPC1 is the target of the cholesterol-lowering drug ezetimibe, and URAT1 is the target of the gout drug lesinurad. Many novel transporter-targeting approaches are also under extensive investigation. Some examples include blocking tumor growth through inhibiting nutrient/amino acid transporters (such as GLUTs, MCTs, ASCT2, and ATB0,+), controlling cellular oxidative stress through targeting xCT, treating schizophrenia by inhibiting asc-1 or Glyt1/Glyt2, and reducing bile acid reabsorption by blocking ASBT. Most recently, evidence emerged for preventing virus cellular entry by blocking their transporter-docking mechanism (e.g. HBV-NTCP, ebola-NPC1).
Transporters As Toxicity Targets
Numerous genetic diseases are known to be caused by the aberrant activities of transporters playing key roles in physiological processes [4,6]. Therefore, the unexpected interactions of drugs with these transporters can lead to serious adverse effects. For example, neurotoxins (e.g. BMAA, ODAP) that inhibit glutamate transporters (e.g., EAATs and xCT) in the brain can lead to fetal acute brain damage and chronic neurological diseases. Drugs such as troglitazone and benzbromarone that inhibit hepatic bile salt transporters (BSEP and NTCP) ) are associated with cholestasis/hepatitis. Recent studies using the JAK2 inhibitor fedratinib had the off-target effect of blocking the thiamine transporters THTR1 and THTR2, leading to encephalopathy.
On the other hand, a less recognized effect is the involvement of transporters in the induction of drug toxicity due to undesired drug accumulation in organs such as kidney and liver. For instance, certain platinum drugs induce severe nephrotoxicity as a result of unwanted platinum accumulation in the kidney due to uptake by OCT2, which could potentially be prevented by addition of specific OCT2 inhibitors. Using similar strategies, it should be possible to decrease the toxicity of numerous marketed drugs that currently show undesirable accumulation in various tissues and organs, including heart, liver, and brain.
Transporters as Delivery Targets
Finally, since many transporters are tissue-specific/tissue-enriched (e.g. OATP1B1 in liver, OCT2 in kidney) or dysregulated in diseases (e.g. GLUT1 and ASCT2 in cancer, DAT in Parkinson’s), transporters can provide novel ways to achieve efficient and targeted intracellular delivery of drugs and imaging agents. Transporter-targeting approaches can be particularly attractive for intracellular drug delivery or prodrug designs as they circumvent the formidable challenge of endosomal escape faced by receptor-mediated endocytosis. One example comes from the class of nucleoside analog drugs (e.g. gemcitabine, 5-FU, zidovudine). These drugs rely on nucleoside transporters CNTs/ENTs for efficient cellular uptake. Therefore, expression levels of these transporters are an important determinant of treatment efficacy. Additional examples include: Lipid lowering statins which exploit OATP1B1/OATP1B3 for liver targeting, the anti-cancer drugs methotrexate and pemetrexed which utilize the vitamin transporters PCFT and RFC for tumor targeting, and several intestinal transporters that have been targeted in prodrug design for improving bioavailability (e.g. PEPT1/valacyclovir, MCT1/gabapentin enacarbil and ASBT/CDCA-glu-gabapentin).Transporters are also important targets for diagnostic imaging. The most successful PET imaging probe, 18F-FDG, is transported by GLUT1, a glucose transporter up-regulated in many cancers; several other cancer imaging probes also target transporters that are enriched in tumors (e.g. NET/123I-MIBG, LAT1/18F-FET, xCT/BAY-94-9392). In addition to tumor imaging, several probes (e.g., 11C-PE2I, 11C-HED ,123 I-ADAM and 18F-FBT) targeting transporters (such as NET, DAT, SERT, VMAT and VAChT) are under development for detecting various neurological disorders, diabetes, and cardiovascular diseases. Similar to the GPCR targets that changed the pharmaceutical industry 25 years ago, membrane transporters represent enormous potential as therapeutic and diagnostic targets for various diseases.